Is HRAS p.Glu126= (c.378A>G) pathogenic?

HRAS p.Glu126= (c.378A>G) is classified Benign in HRAS (ClinVar, Expert panel, 9 submitters; last evaluated 2017-04-18). Rare (popmax 0.144%, sas); Associated with RASopathy.

What condition is associated with HRAS p.Glu126= (c.378A>G)?

HRAS p.Glu126= (c.378A>G) is associated with RASopathy, Costello syndrome, Noonan syndrome and Noonan-related syndrome (ClinVar).

How common is HRAS p.Glu126= (c.378A>G) in the general population?

HRAS p.Glu126= (c.378A>G) is rare (popmax 0.144%, sas) (gnomAD).

HRAS p.Glu126=

c.378A>G · rs397517140 · VCV40442

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.144%, sas)

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Benign for RASopathy. Applied ACMG criteria (verbatim):

BA1

Curation rationale (ClinGen, verbatim)

The filtering allele frequency of the c.378A>G (p.Glu126=) variant in the HRAS gene is 0.095% (23/16510) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -3.7, phastCons 1
Overall
CADD	8.96	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.144% South Asian · 131/91,084 alleles

Filtering AF 0.124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.116%

Overall 0.0113% 182/1,613,784 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.144%	695
Remaining individualsnot grpmax-eligible	0.0048%	20,832
European (non-Finnish)	0.00398%	25,106
East Asian	0.00223%	44,882

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: HRAS
Protein: p.Glu126=
Coding: c.378A>G
MANE Select: NM_005343
dbSNP: rs397517140
Type: single nucleotide variant
Location: chr11:533525 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 256 PDB

Full HRAS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

RASopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Costello syndrome Noonan syndrome and Noonan-related syndrome

Similar variants

HRAS p.Glu126Gln Uncertain significance ★★ ⚠ same residue
HRAS p.Glu126Gly Uncertain significance ★ ⚠ same residue
HRAS p.Glu126Ter Uncertain significance ★ same residue
HRAS p.Ala59Thr Likely pathogenic ★★★ same condition
HRAS p.Gly12Ser Pathogenic ★★★ same condition
HRAS p.Gly13Cys Pathogenic ★★★ same condition
HRAS p.Lys117Arg Pathogenic ★★★ same condition
HRAS p.Thr58Ile Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/hras-p-glu126 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown